rs780953224

chr8-60781069-C-Achr8-60781069-C-Gchr8-60781069-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_017780.4(CHD7):c.1735C>A(p.Gln579Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,457,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q579E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CHD7 NM_017780.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.86

Genes affected

CHD7 (HGNC:20626): (chromodomain helicase DNA binding protein 7) This gene encodes a protein that contains several helicase family domains. Mutations in this gene have been found in some patients with the CHARGE syndrome. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CHD7
• BP4: Computational evidence support a benign effect (MetaRNN=0.1846346).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHD7	NM_017780.4	c.1735C>A	p.Gln579Lys	missense_variant	3/38	ENST00000423902.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD7	ENST00000423902.7	c.1735C>A	p.Gln579Lys	missense_variant	3/38	5	NM_017780.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457798 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 724804

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

CHARGE syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 09, 2020

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CHD7 protein function. This variant has not been reported in the literature in individuals with CHD7-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamine with lysine at codon 579 of the CHD7 protein (p.Gln579Lys). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and lysine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
Cadd	Uncertain	24
Dann	Benign	0.87
DEOGEN2	Benign	0.098	T;.
Eigen	Benign	-0.017
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.81	L;L
MutationTaster	Benign	0.95	D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.67	N;N
REVEL	Benign	0.19
Sift	Benign	0.76	T;T
Sift4G	Benign	0.28	T;T
Polyphen		0.14	B;.
Vest4		0.39
MutPred		0.36		Gain of solvent accessibility (P = 4e-04);Gain of solvent accessibility (P = 4e-04);
MVP		0.80
MPC		0.14
ClinPred		0.36	T
GERP RS		5.2
Varity_R		0.18
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-61693628;